Influence of donors’ cigarette smoking on recipients’ postoperative survival and complications after simultaneous pancreas-kidney transplantation

Many pancreatic transplant donors have smoking history. We aimed to evaluate the effect of donors’ smoking on recipient survival rates and postoperative complications. Patients(N=6564) from the Scientific Registry of Transplant Recipients database who underwent simultaneous pancreas-kidney transplants (SPK) were divided into a cigarette group (n=5465) and non-cigarette group (n=799) based on their donors’ smoking history. Patients’ rates of overall and graft survival were compared and analyzed using the log-rank test. Hazard ratios were estimated using Cox proportional hazards models, and postoperative complications and dialysis times were evaluated using logistics analysis. was not meaningful. However, our findings suggest the cigarette smoking was a risk factor for a higher infection rate after the transplant.


Background
Many pancreatic transplant donors have smoking history. We aimed to evaluate the effect of donors' smoking on recipient survival rates and postoperative complications.

Methods
Patients(N=6564) from the Scientific Registry of Transplant Recipients database who underwent simultaneous pancreas-kidney transplants (SPK) were divided into a cigarette group (n=5465) and non-cigarette group (n=799) based on their donors' smoking history. Patients' rates of overall and graft survival were compared and analyzed using the log-rank test. Hazard ratios were estimated using Cox proportional hazards models, and postoperative complications and dialysis times were evaluated using logistics analysis.

Results
The overall survival and graft survival of the patients in the non-cigarette group were significantly higher compared to those in the cigarette group ( P <0.05 for both log-rank tests). Cigarette smoking among the donors was associated with a significant difference in the recipients' rate of pancreas graft survival and kidney graft survival ( P <0.05 for both log rank-tests). However, multivariate analyses indicated that donors' smoking history was not an independent factor, while the donors' age was associated with reduced survival (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.93-1.28; P =0.287). The cigarette group had a higher postoperative infection rate than the non-cigarette group (HR, 1.45; 95% CI, 1.02-2.06; P =0.038).

Conclusions
Donors' smoking history has no overall effect on rates of overall or graft survival of SPK transplant recipients. However, it should be evaluated before transplantation because of its higher rate of postoperative complications.

Background
Cigarette smoking has been deemed a societal problem due to its harm to smokers and second-hand smokers. Tobacco smoke and involuntary smoking have been confirmed by research to be important pre-tumor factors [1], which cause multiple chronic diseases, especially cardiovascular and pulmonary damage. Based on the prediction of Jha, approximately 450 million adults will die from the effects of smoking between 2000 and 2050[2]. Governments and societies have been raising taxes, enforcing stricter regulations on smoking and supplying more information for consumers to decrease its prevalence. However, many factors also entice people to smoke. To some degree, citizens must cope with higher social anxiety because of the widening wealth gap and faster pace of life. The experience of peer-victimization, depression and social marginalization has been reported to be associated with an increase some individuals' tendency to indulge in drug and tobacco use [3]. The prevalence of smoking has been gradually decreasing because of the efforts of governments and societies,  [6]. Therefore, pancreatic transplants has been regarded as the gold standard of therapy for DM. Compared with liver and heart transplants, patients with DM could survive longer wait-list times for pancreatic transplants with the help of insulin and dialysis, and they had confidence in their ability to meet the stricter criteria for pancreas transplantation. Thus, SPK related risk factors have been receiving increased attention in the research literature to promote better prognoses and preclinical decision-making.
It has been reported that transplantation recipients who smoke before or after a transplant show a significant decrease in survival rates and an increase in surgery complications [7]. There is also a substantial number of donors with a history of cigarette use. For kidney transplants, some research supports the premise that donors who smoke cigarette increase recipients' overall death rates [8] and reduce their graft survival [9], while others predict higher rates of peri-operative complications [10].
For liver transplants, donor smoking has been reported to have a risk ratio as high as 1.249 for overall survival but no effect on graft survival [11]. However, there is paucity of research on the effects cigarette smoking on pancreas and SPK. Thus, we collected and analyzed clinical data, aiming to estimate the effect of donors' history of cigarette smoking on recipients' rate of overall and graft survival. recipients, or pre-transplant history were deleted from the cohort. Patients' records with missing survival data were excluded from the study, as well as the records with missing information on cigarette history. This study was exempt from institutional review board approval at our institution.
Data from the 6264 patients were divided into two study groups: the cigarette group(n = 5465) and non-cigarette group(n = 799) based on their donor's cigarette-use history. The donor cigarette-use history was defined as smoking more than 20 packs of cigarettes per year. The recipients' and donors' characteristics are represented in Table 1.

Donors
The donors' characteristics were also compared between groups, including age, gender, ethnicity, BMI, cause of death, death from stroke, desmopressin acetate (DDAVP) before the transplant, expanded kidney criteria, history of hypertension, serum creatinine, warm ischemia time (WIT) and cold ischemia time (CIT). Ethnicity was classified using the same categories as those used for the recipients. Cause of the donor's death was classified as anoxia, cerebrovascular accident, head trauma, and others. Hypertension was defined as a systolic pressure greater than 160 mmHg or a diastolic pressure greater than 90 mmHg. Serum creatinine level were retrieved from the participants' most recent records before surgery.

Statistical analysis
Continuous and categorical variables were compared using Student's t-test and the chi-square test, respectively. The results were reported as mean ± standard deviation unless otherwise indicated. An alpha level of 0.05 indicated statistical significance. The Kaplan-Meier method was used to compare patients' overall and graft survival. Log-rank tests and multivariate Cox proportional hazard regression analyses were performed to obtain survival curves and for multivariate analyses.
Univariate and multivariate Cox proportional hazards regressions of the entire cohort were performed to identify the predictors. A p value < 0.05 was considered statistically significant in univariate analysis as showed in Table 1. All factors with p values < 0.1 in the univariate analysis were selected for inclusion in the multivariate model. All statistical analyses were performed using SPSS 20.0 (IBM Corp, Armonk, NY).
A significant difference was found between two groups of donors (smokers and non-smokers) by age, gender, ethnicity, cause of death, stroke, DDVAP, expanded kidney criteria, hypertension and WIT.
However, no significant difference in BMI or Serum creatinine > 1.5 was found between the two groups. These findings might be related to the epidemiology of the donors' cigarette use and selection bias. Since we defined the cigarette group as those who smoked more than 20 packs of cigarette per year, the average age should have been older than those of the non-cigarette group, which had more teenagers. Males are more likely to smoke whereas females find it harder to quit [12], but in our study, there were more males in the non-cigarette group (P < 0.01). Differences in gender between the two groups might be related not only to gender bias in the prevalence of smoking but also to donor pairing and selection bias. Though smoking is usually associated with a higher body weight [13], the criteria for donors might have offset this association because over-weight donors were not selected for transplants. Thus, no differences were found between two groups. Furthermore, the cigarette use can also lead to hypertension, a higher resting heart rate [14], worse kidney function [15] and harm to the cardiovascular system [12]. Thus, in the cigarette group, there were higher proportions of deaths by stroke and other cardiovascular accident, which also led to the more frequent use of DDAVP for the treatment of donors. Given the characteristics of the cigarette group, the differences in cause of death, stroke, DDAVP, expanded kidney criteria and hypertension might have been related to or caused by cigarette smoking, thus, these variables were not included in the multivariate analysis. In this study, only the donors' age, and the donors' and recipients' gender, BMI, exocrine and endocrine drainage, PRA > 20%, and ethnicity were included in the multivariate analysis. The results of the Cox analysis, which was performed to identify the independent effect of cigarettes, are presented showed in Table 2. Although the univariate analysis showed significant differences between the two groups in their overall, graft, kidney and pancreas survival, the multivariate analysis showed that the donors' cigarette usage had no significant effect on the recipients' overall, graft, pancreas and kidney survival (P > 0.05). We thought the differences between the two groups were mainly caused by their different ages. The significant difference in age between the two groups of donors was due to the study's criteria for cigarette use (20 packs of cigarette smoked per year).
Donors who were non-smokers were much younger than those who smoked and the curve of the smokers showed a bimodal distribution (Fig. 2). To control for bias of donors' age, the survival rates of the two groups were analyzed by their age categories (Fig. 3A-F, 4 A-F,5 A-F and 6 A-F  The recipients in the cigarette group had a longer hospital stay than those in the non-cigarette group (P < 0.05), as seen in Fig. 7.
The frequency of each variable and results of the multivariate analysis of the recipients' complications, including rejection, pancreatitis, infection, leaks, thrombosis and bleeding are showed in Table 3. The morbidities of infection and thrombosis were significant different between the two groups. However, due to the large amount of missing data (90%) on thrombosis (thrombosis data for only 384 individuals were found in the database), the difference between the groups was not meaningful. However, our findings suggest the cigarette smoking was a risk factor for a higher infection rate after the transplant. Thus, it is necessary to examine the survival rates of patients who receive organs from smoking donors.
In our study, the multivariable analysis showed donors' cigarette history had no effect on overall or graft survival. However, post-transplant complications increased due to the donors' cigarette history.
The results of a kidney transplant, study on living donors supported a higher death rate among smoking donors [17]. When deceased donors were included, the effect of donors' smoking history decreased [18]. Our results found little difference between the two groups, which might have been due to the donor source for the SPK. The organs donated for SPK, which are usually from deceased donors, are more likely to have been exposed to longer ischemia times and other potential injuries compared to the organs of living donor transplants, and SKP have stricter criteria for donors than do kidney and other types of pancreas transplants [19]. Thus, it is possible that the stricter criteria for donors also excluded most injured organs, decreasing the risk for death related to cigarette smoking history.
The significant differences in overall, graft and kidney survival found in the Kaplan-Meier analysis were mainly related to donors' age, which has been confirmed as a risk factor for death [20,21].
However, only a small difference between the smoking and non-smoking donors was found when the donors' age was analyzed by subgroups. For the different age groups, no significant difference between any two groups was found until data from donors older than 50 years old were analyzed.
Perhaps these results are related to the chronic damage caused by cigarette smoking, as older smokers are more likely to have a much longer history than younger smokers are, which is a worthwhile issue for further investigation.
Though donors' cigarette smoking history had no effect on graft or overall survival, it did influence

Availability of data and material:
The data that support the findings of this study are available from the Scientific Registry of Transplant Recipients database, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.
Data are however available from the authors upon reasonable request and with permission of the Scientific Registry of Transplant Recipients database.

Competing interests:
The authors declare that they have no competing interests.  Kaplan-Meier analysis of overall survival, graft survival, kidney and pancreas survival.

Figure 2
Distribution of donors according to their age.

Figure 3
Survival curves of the two groups by their age categories (patient).

Figure 4
Survival curves of the two groups by their age categories (kidney).

Figure 5
Survival curves of the two groups by their age categories (pancreas).

Figure 6
Survival curves of the two groups by their age categories (graft).

Figure 7
The comparison of hospital stays for cigarette group and non-cigarette group.